The present invention relates to oral controlled release dosage formulations containing an analgesic. More specifically, the present invention relates to an oral dosage formulation in the form of a capsule, tablet or pellet comprising a water soluble analgesic such as tramadol or its pharmaceutically acceptable derivatives which are described in U.S. Pat. Nos. 5,516,803, 5,336,691 and 5,468,7442 and are incorporated herein by reference.
In the prior art are extended release tablets which have an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the membrane. If the active ingredient is insoluble in the permeating fluid, a hydrogel is employed to push the active ingredient through the passageway. Some representative examples of these osmotic tablet systems can be found in U.S. Pat. Nos. 3,845,770, 3,916,899, 3,952,741, 4,034,758, 4,077,407 and 4,783,337.
The basic osmotic device described in the above-cited patents has been refined over time in an effort to provide greater control of the release of the active ingredient. For example U.S. Pat. Nos. 4,777,049 and 4,851,229 describe an osmotic dosage form comprising a semipermeable wall surrounding a core. The core contains an active ingredient and a modulating agent wherein the modulating agent causes the active ingredient to be released through a passageway in the semipermeable membrane in a pulsed manner. Further refinements are described in U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 which include modifications to the semipermeable membrane surrounding the active core or as described in U.S. Pat. Nos. 5,650,170 and 4,892,739 which include increasing the number of coatings surrounding the active core.
Also in the prior art are techniques for preparing controlled release formulations that comprise encapsulating a plurality of beads or pellets coated with a diffusion barrier such as U.S. Pat. Nos. 5,376,384, 5,529,790, 5,470,584, 5,002,776, 5,445,829, 5,578,321, 4,524,060, 4,752,470. These patents teach obtaining a controlled release of an active ingredient by varying the coating level of the diffusion barriers and/or the composition of the diffusion barriers. These patents also teach the combination of beads with varying release profiles to obtain a desired composite release profile.
None of the above described prior art references suggest a controlled release formulation that employs the drug tramadol or its pharmaceutically acceptable derivatives as the active ingredient. Further none of the above-cited patents suggest an osmotic tablet or pellet with a unitary core that does not contain a binding agent or an expanding agent.
Tramadol, (1R, 2R or 1S, 2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol, is a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring which is described in greater detail in U.S. Pat. No. 3,652,589 and incorporated herein by reference. Tramadol is believed to produce an analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like because clinical data suggests that tramadol lacks many of the typical side effects of opioid antagonists such as respiratory depression, constipation, tolerance and abuse liability but can produce hot flashes and sweating. Due to combination of non-opioid and opioid activity, tramadol is a very unique analgesic and many attempts have been made to prepare oral formulations of the drug. For example an immediate release oral formulation of tramadol is commercially available from McNeil Pharmaceuticals under the tradename ULTRAM.RTM..
The 50th Edition of the Physician's Desk Reference, copyright 1996, p. 1585, states that peak plasma levels for the ULTRAM.RTM. product occur about two (2) hours after dosing but this time can vary slightly depending upon the racemic mixture of tramadol employed in the dosage form. Other attempts at preparing useful dosage forms of tramadol have been directed to combining tramadol with other drugs such as non-steroidal anti-inflammatory drugs, acetaminophen or codeine as described in U.S. Pat. Nos. 5,516,803, 5,468,744 and 5,336,691.
Attempts have also been made to formulate tramadol into controlled release formulations such as those described in: U.S. Pat. Nos. 5,395,626, 5474,786 and 5,645,858 which employ a plurality of coating layers to control the release of tramadol over time; U.S. Pat. Nos. 5,580,587 and 5,639,476 which employ a coating of an aqueous dispersion of hydrophobic acrylic polymers dried for an extended period of time under rigid conditions; U.S. Pat. Nos. 5,601,842 and 5,591,452 which employ a polymer matrix to control the release of the drug; and European Patent Application No. 147 780 which employs a super hydrolyzed polyvinyl alcohol coating that gels in the aqueous environment of the body and controls the release of the drug. These controlled release formulations for tramadol are very labor intensive to prepare.
It is an object of the present invention to provide a controlled or sustained release dosage formulation for an analgesic that is easy to manufacture and can be used to prepare a range of dosing levels.
It is a further object of the present invention to provide a controlled or sustained release dosage formulation for an analgesic that does not obtain peak plasma levels for at least four (4) hours, preferably six to twenty hours and most preferably ten to eighteen hours, after administration.
It is also a further object of the present invention to provide a controlled or sustained release dosage formulation for an analgesic that does not employ an expanding polymer or a binding agent.
It is also a further object of the present invention to provide a controlled or sustained release dosage formulation for an analgesic that can be prepared with only one or two coating layers.
It is an additional object of the present invention to provide a controlled or sustained release dosage formulation for an analgesic that can provide continuous and non-pulsating therapeutic levels of the analgesic to an animal or human in need of such treatment over a twelve hour to twenty-four hour period.
It is also an object of this invention to provide a controlled or sustained release pharmaceutical tablet or pellet having only a homogeneous osmotic core wherein the osmotic core component may be made using ordinary tablet compression techniques.
It is also an object of this invention to provide a controlled or sustained release pharmaceutical formulation comprising an immediate release tablet or pellet and a controlled release tablet or pellet.